The present invention relates to new dihydrofuro[3,4-b]quinolin-1-one compounds, and to the use thereof as anti-cancer agents.
The requirements of anti-cancer therapeutics call for the constant development of new anti-tumour agents, with the aim of obtaining medicaments that are both more active and better tolerated.
The compounds of the invention are not only new but have very valuable anti-tumour properties.
Compounds of a similar structure have already been described in the literature, notably furo[3,4-b]quinolin-1-one compounds as anti-osteoporotics (patent EP 0 634 169).
On the other hand, a cytotoxic activity has never been described for those compounds.
The present invention relates more especially to compounds of formula (I): 
wherein:
 represents a single or double bond,
R0 represents a hydrogen atom, a hydroxy group or a linear or branched (C1-C6)alkoxy group,
R1 and R2, which are identical or different, each represents:
a hydrogen atom,
a halogen atom,
a linear or branched (C1-C6)alkyl group,
a linear or branched (C1-C6)alkoxy group,
a hydroxy group,
a linear or branched (C1-C6)polyhaloalkyl group,
a nitro group,
an amino group optionally substituted by one or two linear or branched (C1-C6)-alkyl groups,
a group of formula 
xe2x80x83wherein m represents an integer such that 1xe2x89xa6mxe2x89xa64, or form together with the carbon atoms carrying them an aromatic or non-aromatic, mono- or bi-cyclic group having from 5 to 12 ring members, optionally containing 1 or 2 hetero atoms selected from O, S and N,
R3 represents a hydrogen atom or a group of formula R4 wherein R4 represents:
an aryl group,
a heteroaryl group,
a (C3-C8)cycloalkyl group,
a linear or branched (C1-C6)alkyl group optionally substituted by an aryl group, by a heteroaryl group, by a hydroxy group, by a linear or branched (C1-C6)alkoxy group, or by a group of formula NR5R6 wherein R5 and R6, which are identical or different, each represents a linear or branched (C1-C6)alkyl group or a linear or branched (C1-C6)hydroxyalkyl group, or form together with the nitrogen atom carrying them a nitrogen heterocycle,
or a group of formula COR7, wherein R7 represents one of the following groups:
aryl,
linear or branched (C1-C6)alkyl (optionally substituted by a group of formula NR8R9 wherein R8 and R9, which are identical or different, each represents a linear or branched (C1-C6)alkyl group or a linear or branched (C1-C6)hydroxyalkyl group, or form together with the nitrogen atom carrying them a nitrogen heterocycle),
amino optionally substituted by one or more groups aryl, heteroaryl, or linear or branched (C1-C6)alkyl optionally substituted by a group of formula NR8R9 wherein R8 and R9, which are identical or different, each represents a linear or branched (C1-C6)alkyl group or a linear or branched (C1-C6)-hydroxyalkyl group, or form together with the nitrogen atom carrying them a nitrogen heterocycle,
or OR10 wherein R10 represents a hydrogen atom or a group aryl, or linear or branched (C1-C6)alkyl optionally substituted by a group of formula NR8R9 wherein R8 and R9, which are identical or different, each represents a linear or branched (C1-C6)alkyl group or a linear or branched (C1-C6)hydroxyalkyl group, or form together with the nitrogen atom carrying them a nitrogen heterocycle,
X represents an oxygen or sulphur atom or a xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94 group,
Ar represents an aryl, heteroaryl or aryl-(C1-C6)alkyl group in which alkyl is linear or branched,
their optical isomers, addition salts thereof with a pharmaceutically acceptable acid, and hydrates and solvates thereof.
Among the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric, hydrobromic, sulphuric, phosphoric, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, oxalic, methanesulphonic, benzenesulphonic and camphoric acid.
An aryl group is to be understood as phenyl, biphenyl, naphthyl or tetrahydronaphthyl, each of those groups being optionally substituted by one or more identical or different atoms or groups selected from halogen atoms and the groups linear or branched (C1-C6)-alkyl, hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)polyhaloalkyl, amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups), nitro, linear or branched (C1-C6)acyl and (C1-C2)alkylenedioxy.
A heteroaryl group is to be understood as an aromatic, mono- or bi-cyclic group having from 5 to 12 ring members and containing one, two or three hetero atoms selected from oxygen, nitrogen and sulphur, wherein the heteroaryl group may be optionally substituted by one or more identical or different atoms or groups selected from halogen atoms and the groups linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, linear or branched (C1-C6)polyhaloalkyl, and amino (optionally substituted by one or more linear or branched (C1-C6)alkyl groups). Among the heteroaryl groups there may be mentioned, without implying any limitation, the groups thienyl, pyridyl, furyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, quinolyl, isoquinolyl and pyrimidinyl.
A nitrogen heterocycle is to be understood as a saturated monocyclic group having from 5 to 7 ring members and containing one, two or three hetero atoms, one of which is nitrogen while the additional hetero atom(s) optionally present is/are selected from oxygen, nitrogen and sulphur. Preferred nitrogen heterocycles are the groups pyrrolidinyl, piperidyl, morpholinyl and piperazinyl.
Among the aromatic or non-aromatic, mono- or bi-cyclic groups having from 5 to 12 ring members and optionally containing 1 or 2 hetero atoms selected from O, S and N there may be mentioned, without implying any limitation, the groups phenylene, naphthylene, cyclopentenylene and the groups of formulae G1 to G5: 
Preferred compounds of formula (I) are those wherein  represents a double bond.
Preferred compounds of formula (I) are those wherein R0 represents a hydrogen atom.
An advantageous embodiment of the invention relates to compounds of formula (I) wherein R1 and R2, which are identical or different, each represents
a hydrogen atom,
a halogen atom,
a linear or branched (C1-C6)alkyl group,
a linear or branched (C1-C6)alkoxy group,
a hydroxy group,
a linear or branched (C1-C6)polyhaloalkyl group,
a nitro group,
an amino group optionally substituted by one or two linear or branched (C1-C6)-alkyl groups, or
a group of formula 
xe2x80x83wherein m represents an integer such that 1xe2x89xa6mxe2x89xa64.
Another advantageous embodiment of the invention relates to compounds of formula (I) wherein R1 and R2 form together with the carbon atoms carrying them an aromatic or non-aromatic, mono- or bi-cyclic group having from 5 to 12 ring members and optionally containing 1 or 2 hetero atoms selected from O, S and N.
Among these are most preferred those wherein R1 and R2 together form, with the carbon atoms carrying them, a phenylene group or a group of formula G3 or G4 as defined hereinbefore.
Another advantageous embodiment of the invention relates to compounds of formula (I) wherein X represents an oxygen or sulphur atom.
Another advantageous embodiment of the invention relates to compounds of formula (I) wherein X represents a xe2x80x94CH2xe2x80x94 or xe2x80x94CH2xe2x80x94CH2xe2x80x94 group.
Another advantageous embodiment of the invention relates to compounds of formula (I) wherein Ar represents an aryl group, more preferably an optionally substituted phenyl group.
Another advantageous embodiment of the invention relates to compounds of formula (I) wherein Ar represents a heteroaryl group.
Among the preferred compounds of the invention, there may be mentioned:
(xc2x1)-4-methyl-6,7-methylenedioxy-9-(3,4,5-trimethoxyphenyl)-4,9-dihydrofuro[3,4-b]quinolin-1(3H)-one, and also its optical isomers and its hydrates and solvates,
(xc2x1)-6,7-methylenedioxy-9-(3,4,5-trimethoxyphenyl)-4,9-dihydrofuro[3,4-b]quinolin-1(3H)-one, its optical isomers, its hydrates, solvates, and also its addition salts with a pharmaceutically acceptable acid,
(xc2x1)-6-methoxy-9-(3,4,5-trimethoxyphenyl)-4,9-dihydrofuro[3,4-b]quinolin-1(3H)-one, its optical isomers, its hydrates solvates, and also its addition salts with a pharmaceutically acceptable acid,
(xc2x1)-7-(3,4,5-trimethoxyphenyl)-7,11-dihydrobenzo[h]furo[3,4-b]quinolin-8(10H)-one, its optical isomers, its hydrates, solvates, and also its addition salts with a pharmaceutically acceptable acid,
(xc2x1)-6,7-methylenedioxy-9-(3,4,5-trimethoxyphenyl)-2,3,4,9-tetrahydrocyclopenta[b]quinolin-1-one, its optical isomers, its hydrates, solvates, and also its addition salts with a pharmaceutically acceptable acid,
(xc2x1)-6,7-ethylenedioxy-9-(3,4,5-trimethoxyphenyl)-4,9-dihydrofuro[3,4-b]quinolin-1(3H)-one, its optical isomers, its hydrates, solvates, and also its addition salts with a pharmaceutically acceptable acid,
and (xc2x1)-7-(3,4,5-trimethoxyphenyl)-7,9,10,11-tetrahydro-8H-benzo[h]cyclopenta[b]quinolin-8-one, its optical isomers, its hydrates, solvates, and also its addition salts with a pharmaceutically acceptable acid.
The invention relates also to a process for the preparation of the compounds of formula (I) which is characterised in that a compound of formula (II): 
wherein R0, R1, R2 and R3 have the same meanings as for formula (I),
is reacted with a compound of formula (III): 
wherein X and Ar have the same meanings as for formula (I),
to yield a compound of formula (Ia), a particular case of the compounds of formula (I): 
wherein R0, R1, R2, R3, X and Ar are as defined hereinbefore,
which is then reduced, if desired, to a compound of formula (Ib), a particular case of the compounds of formula (I): 
wherein R0, R1, R2, R3, X and Ar are as defined hereinbefore,
which compounds of formulae (Ia) and (Ib), which constitute the totality of the compounds of formula (I), are purified, if necessary, according to a conventional purification technique, are separated, if desired, into their optical isomers according to a conventional separation technique, and are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid.
When R3 does not represent a hydrogen atom, the compound of formula (II) can be obtained by reaction of a compound of formula (IV): 
wherein R0, R1 and R2 are as defined hereinbefore,
with a compound of formula (V):
R4xe2x80x94Yxe2x80x83xe2x80x83(V)
wherein R4 has the same meanings as for formula (I) and Y represents a leaving group, such as, for example, a halogen atom or a mesylate, tosylate or trifluoromethane-sulfonate group.
When R3 represents a group of formula xe2x80x94CH2Rxe2x80x23 wherein Rxe2x80x23 represents an aryl group, a heteroaryl group or a linear or branched (C1-C5)alkyl group optionally substituted by an aryl group, by a heteroaryl group, by a hydroxy group, by an optionally substituted, linear or branched (C1-C6)alkoxy group, or by a group of formula NR5R6 wherein R5 and R6, which are identical or different, each represents a linear or branched (C1-C6)-alkyl group or a linear or branched (C1-C6)hydroxyalkyl group, or form together with the nitrogen atom carrying them a nitrogen heterocycle, the compound of formula (II) can likewise be obtained by reaction, in the presence of a reducing agent, of a compound of formula (IV) with a compound of formula (VI): 
wherein Rxe2x80x23 is as defined hereinbefore.
When R3 represents a group of formula xe2x80x94CORxe2x80x27 wherein Rxe2x80x27 represents an aryl group, the compound of formula (II) can likewise be obtained by reaction of a compound of formula (VII): 
wherein R0, R1, R2 and Rxe2x80x27 are as defined hereinbefore,
with an oxidizing agent.
When R3 represents a CH3 group, the compound of formula (II) can likewise be obtained by reaction of a compound of formula (IV) with formic acid in the presence of a reducing agent.
The compound of formula (III) is obtained by reaction of a compound of formula (VIII): 
wherein Ar is as defined hereinbefore,
with a compound of formula (IX): 
wherein X is as defined hereinbefore,
in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541.
The invention extends also to a second process for the preparation of the compounds of formula (I), which is characterised in that there are reacted, in the same pot, a compound of formula (II), a compound of formula (VII) and a compound of formula (VIII),
to yield a compound of formula (Ia), which is then reduced, if desired, to a compound of formula (Ib),
which compounds of formulae (Ia) and (Ib), which constitute the totality of the compounds of formula (I), are purified, if necessary, according to a conventional purification technique, are separated, if desired, into their optical isomers according to a conventional separation technique, and are converted, if desired, into addition salts thereof with a pharmaceutically acceptable acid.
The compounds of the present invention are not only new but exhibit valuable pharmacological properties. They exhibit cytotoxic properties, rendering them useful in the treatment of cancers.
The invention extends also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) with one or more appropriate, inert, non-toxic excipients. Among the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous) or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, injectable preparations, drinkable suspensions, etc.
The useful dosage can be adapted in accordance with the nature and severity of the disorder, the administration route, the age and weight of the patient, and possibly associated treatments. The posology varies from 0.5 mg to 2 g per 24 hours taken in one or more administrations.
The following Examples illustrate the invention but do not limit it in any way.
The starting materials employed are known products or products prepared in accordance with known preparation procedures.
Preparations A to S result in synthesis intermediates for use in the preparation of the compounds of the invention.
The structures of the compounds described in the Examples were determined in accordance with customary spectrometric techniques (infra-red, NMR, mass spectrometry).
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 3,4,5-trimethoxybenzaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 4-hydroxy-3,5-dimethoxybenzaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from nicotinaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 3-methoxy-4,5-methylenedioxybenzaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 2,3,4-trimethoxybenzaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 3,4-dimethoxybenzaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 3-hydroxy-4-methoxybenzaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 4-methoxybenzaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 3-methoxybenzaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from benzaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978. 43, 1541, starting from 2-furaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 3,4,5-trimethoxybenzaldehyde and 1,3-cyclopentane-dione.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 4,5-methylenedioxybenzaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 4-chlorobenzaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 4-nitrobenzaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 3-nitrobenzaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 4-dimethylaminobenzaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from isonicotinaldehyde and tetronic acid.
The expected product is obtained in accordance with the procedure described in J. Org. Chem. 1978, 43, 1541, starting from 2-pyridinecarboxaldehyde and tetronic acid.